Members of the tumor necrosis factor (TNF) superfamily play cardinal roles in inflammation and autoimmune diseases. TRAIL, that is capable of inducing apoptosis. Our long-term goal of research is to elucidate the mechanisms of action of TNF-related apoptosis-inducing proteins in autoimmune diseases. This proposal is based on our recent discovery that TRAIL is an anti-inflammatory member of the TNF family. Mice deficient in TRAIL had an increased susceptibility to type I diabetes, and TRAIL-blockade in NOD mice significantly accelerated the disease and enhanced anti-GAD65 T cell responses. The goals of this proposal are to elucidate the mechanisms of TRAIL action in type I diabetes mellitus and to manipulate TRAIL functions for the treatment of the disease. A major challenge to study the roles of TNF/TNF-receptor families of proteins is that they are often expressed by a variety of cell types that perform different functions. In the case of TRAIL and its receptors, they are expressed not only by cells of the immune system that mediate inflammation but also by cells of target organs that succumb to immune destruction. Additionally, TRAIL-related apoptotic proteins often activate opposing signaling pathways in cells, which can either promote (through caspase cascade) or prevent (through NF-kappaB or c-Jun) cell death. The roles of TRAIL in different cell types must be established before a comprehensive understanding of its function in autoimmune diseases can be achieved. We hypothesize that the roles of TRAIL in type I diabetes is dictated by its targets and the nature of the signals it generates, and that manipulating TRAIL signals can be effective for the treatment of type I diabetes. To test these hypotheses, we will study 1) the roles of TRAIL expressed by immune cells and non-immune cells, 2) the targets of TRAIL action in type I diabetes, 3) the effects of TRAIL administration and TRAIL gene transfer in vivo, and 4) the relationship between TRAIL and FasL in type I diabetes. Information generated from these studies may not only help elucidate the mechanisms of TRAIL action in type I diabetes but also aid in developing a novel strategy to treat the disease.